bims-mecosi 2024-07-14 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2024‒07‒14
fifteen papers selected by
Verena Kohler, Umeå University

Membrane Curvature Promotes ER-PM Contact Formation via Junctophilin-EHD Interactions.
Impact of DEHP on mitochondria-associated endoplasmic reticulum membranes and reproductive toxicity in ovary.
Patchouli alcohol alleviates metabolic dysfunction-associated steatohepatitis via inhibiting mitochondria-associated endoplasmic reticulum membrane disruption-induced hepatic steatosis and inflammation in rats.
Hesperidin Alleviated Intestinal Barrier Injury, Mitochondrial Dysfunction, and Disorder of Endoplasmic Reticulum Mitochondria Contact Sites under Oxidative Stress.
Cold inducible RNA binding protein-regulated mitochondria associated endoplasmic reticulum membranes-mediated Ca2+ transport play a critical role in hypothermia cerebral resuscitation.
Interorganelle phospholipid communication, a house not so divided.
Daily Light Onset and Plasma Membrane Tethers Regulate Mitochondria Redistribution within the Retinal Pigment Epithelium.
The lipid droplet assembly complex consists of seipin and four accessory factors in budding yeast.
Drp1 Aggravates Copper Nanoparticle-Induced ER-Phagy by Disturbing Mitochondria-Associated Membranes in Chicken Hepatocytes.
The Use of Hexokinase 2-Displacing Peptides as an Anti-Neoplastic Approach for Malignant Peripheral Nerve Sheath Tumors.
Cytochrome b5 reductase 3 overexpression and dietary nicotinamide riboside supplementation promote distinctive mitochondrial alterations in distal convoluted tubules of mouse kidneys during aging.
Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.
The physical basis of analog-to-digital signal processing in the EGFR system-Delving into the role of the endoplasmic reticulum.
Lipid Droplet-Mitochondria Contacts in Health and Disease.
Myocardial transcriptomic analysis of diabetic patients with aortic stenosis: key role for mitochondrial calcium signaling.

bioRxiv. 2024 Jun 30. pii: 2024.06.29.601287. [Epub ahead of print]

Membrane Curvature Promotes ER-PM Contact Formation via Junctophilin-EHD Interactions.

Yang Yang, Luis A Valencia, Chih-Hao Lu, Melissa L Nakamoto, Ching-Ting Tsai, Chun Liu, Huaxiao Yang, Wei Zhang, Zeinab Jahed, Wan-Ru Lee, Francesca Santoro, Jen Liou, Joseph C Wu, Bianxiao Cui.

Contact sites between the endoplasmic reticulum (ER) and the plasma membrane (PM) play a crucial role in governing calcium regulation and lipid homeostasis. Despite their significance, the factors regulating their spatial distribution on the PM remain elusive. Inspired by observations in cardiomyocytes, where ER-PM contact sites concentrate on tubular PM invaginations known as transverse tubules (T-tubules), we hypothesize that the PM curvature plays a role in ER-PM contact formation. Through precise control of PM invaginations, we show that PM curvatures locally induce the formation of ER-PM contacts in cardiomyocytes. Intriguingly, the junctophilin family of ER-PM tethering proteins, specifically expressed in excitable cells, is the key player in this process, while the ubiquitously expressed extended synaptotagmin 2 does not show a preference for PM curvature. At the mechanistic level, we find that the low complexity region (LCR) and the MORN motifs of junctophilins can independently bind to the PM, but both the LCR and MORN motifs are required for targeting PM curvatures. By examining the junctophilin interactome, we identify a family of curvature-sensing proteins, Eps15-homology domain containing proteins (EHDs), that interact with the MORN_LCR motifs and facilitate junctophilins' preferential tethering to curved PM. These findings highlight the pivotal role of PM curvature in the formation of ER-PM contacts in cardiomyocytes and unveil a novel mechanism for the spatial regulation of ER-PM contacts through PM curvature modulation.

DOI: https://doi.org/10.1101/2024.06.29.601287
Ecotoxicol Environ Saf. 2024 Jul 08. pii: S0147-6513(24)00755-3. [Epub ahead of print]282 116679

Impact of DEHP on mitochondria-associated endoplasmic reticulum membranes and reproductive toxicity in ovary.

Qingchun Guo, Taoran Deng, Yaoyao Du, Wen Yao, Wenqu Tian, Hongmei Liao, Yi Wang, Juan Li, Wei Yan, Yufeng Li.

  Di(2-ethylhexyl) phthalate (DEHP) is a widely recognized environmental endocrine disruptor that potentially impacts female reproductive function, although the specific mechanisms leading to such impairment remain unclear. A growing body of research has revealed that the endoplasmic reticulum and mitochondrial function significantly influence oocyte quality. The structure of mitochondria-associated endoplasmic reticulum membranes (MAMs) is crucial for facilitating the exchange of Ca2+, lipids, and metabolites. This study aimed to investigate the alterations in the composition and function of MAMs after DEHP exposure and to elucidate the underlying mechanisms of ovarian toxicity. The female mice were exposed to DEHP at doses of 5 and 500 mg/kg/day for one month. The results revealed that DEHP exposure led to reduced serum anti-Müllerian hormone levels and increased atretic follicles in mice. DEHP induced endoplasmic reticulum stress and disrupted calcium homeostasis in oocytes. Furthermore, DEHP impaired the mitochondrial function of oocytes and reduced their membrane potential, and promoting apoptosis. Similar results were observed in human granulosa cells after exposure to mono-(2-ethylhexyl) phthalate (MEHP, metabolites of DEHP) in vitro. Proteomic analysis and transmission electron microscopy revealed modifications in the functional proteins and structure of the MAMs, and the suppression of oxidative phosphorylation pathways. The findings of this investigation provide a new perspective on the mechanism underlying the reproductive toxicity of DEHP in females.

Keywords:  Calcium homeostasis; DEHP; MAMs; Oocyte; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.ecoenv.2024.116679
Int Immunopharmacol. 2024 Jul 05. pii: S1567-5769(24)01155-X. [Epub ahead of print]138 112634

Patchouli alcohol alleviates metabolic dysfunction-associated steatohepatitis via inhibiting mitochondria-associated endoplasmic reticulum membrane disruption-induced hepatic steatosis and inflammation in rats.

Xingyu Xie, Yingyi Liao, Zixin Lin, Huijuan Luo, Guilan Wei, Ning Huang, Yucui Li, Jiannan Chen, Ziren Su, Xiuting Yu, Liping Chen, Yuhong Liu.

  Metabolic dysfunction-associated steatohepatitis (MASH) is a severe metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by abnormal hepatic steatosis and inflammation. Previous studies have shown that Patchouli alcohol (PA), the primary component of Pogostemonis Herba, can alleviate digestive system diseases. However, its protection against MASH remains unclear. This study explored the protective effects and underlying mechanism of PA against high-fat diet-induced MASH in rats. Results showed that PA considerably reduced body weight, epididymal fat, and liver index and attenuated liver histological injury in MASH rats. PA alleviated hepatic injury by inhibiting steatosis and inflammation. These effects are associated with the improvement of SREBP-1c- and PPARα-mediated lipid metabolism and inhibition of the STING-signaling pathway-mediated inflammatory response. Moreover, PA-inhibited hepatic endoplasmic reticulum (ER) stress and mitochondrial dysfunction, reducing SREBP-1c and STING expressions and enhance PPARα expression. PA treatment had the strongest effect on the regulation of mitogen fusion protein 2 (Mfn2) in inhibiting mitochondrial dysfunction. Mfn2 is an important structural protein for binding ERs and mitochondria to form mitochondria-associated ER membranes (MAMs). MASH-mediated disruption of MAMs was inhibited after PA treatment-induced Mfn2 activation. Therefore, the pharmacological effect of PA on MASH is mainly attributed to the inhibition of MAM disruption-induced hepatic steatosis and inflammation. The findings of this study may have implications for MASH treatment that do not neglect the role of Mfn2-mediated MAMs.

Keywords:  Inflammation; Metabolic dysfunction-associated steatohepatitis; Mitochondria-associated endoplasmic reticulum membrane; Patchouli alcohol; Steatosis

DOI:  https://doi.org/10.1016/j.intimp.2024.112634
J Agric Food Chem. 2024 Jul 09.

Hesperidin Alleviated Intestinal Barrier Injury, Mitochondrial Dysfunction, and Disorder of Endoplasmic Reticulum Mitochondria Contact Sites under Oxidative Stress.

Feiyang Gou, Qian Lin, Xiaodian Tu, Jiang Zhu, Xin Li, Shaokui Chen, Caihong Hu.

  As primary flavonoids extracted from citrus fruits, hesperidin has been attracting attention widely for its capacity to act as antioxidants that are able to scavenge free radicals and reactive oxygen species (ROS). Many factors have made oxidative stress a risk factor for the occurrence of intestinal barrier injury, which is a serious health threat to human beings. However, little data are available regarding the underlying mechanism of hesperidin alleviating intestinal injury under oxidative stress. Recently, endoplasmic reticulum (ER) mitochondria contact sites (ERMCSs) have aroused increasing concerns among scholars, which participate in mitochondrial dynamics and Ca2+ transport. In our experiment, 24 piglets were randomly divided into 4 groups. Piglets in the diquat group and hesperidin + diquat group received an intraperitoneal injection of diquat (10 mg/kg), while piglets in the hesperidin group and hesperidin + diquat group received hesperidin (300 mg/kg) with feed. The results indicated that hesperidin alleviated growth restriction and intestinal barrier injury in piglets compared with the diquat group. Hesperidin ameliorated oxidative stress and restored antioxidant capacity under diquat exposure. The mitochondrial dysfunction was markedly alleviated via hesperidin versus diquat group. Meanwhile, hesperidin alleviated ER stress and downregulated the PERK pathway. Furthermore, hesperidin prevented the disorder of ERMCSs by downregulating the level of ERMCS proteins, decreasing the percentage of mitochondria with ERMCSs/total mitochondria and the ratio of ERMCSs length/mitochondrial perimeter. These results suggested hesperidin could alleviate ERMCS disorder and prevent mitochondrial dysfunction, which subsequently decreased ROS production and alleviated intestinal barrier injury of piglets under oxidative stress.

Keywords:  endoplasmic reticulum mitochondria contact sites; hesperidin; intestinal barrier; mitochondria; oxidative stress

DOI:  https://doi.org/10.1021/acs.jafc.4c02265
Exp Neurol. 2024 Jul 09. pii: S0014-4886(24)00209-7. [Epub ahead of print]379 114883

Cold inducible RNA binding protein-regulated mitochondria associated endoplasmic reticulum membranes-mediated Ca2+ transport play a critical role in hypothermia cerebral resuscitation.

Yu Gao, Haoxin Liu, Yaqing Zhou, Shenquan Cai, Jie Zhang, Jie Sun, Manlin Duan.

  Cardiac arrest is a global health issue causing more deaths than many other diseases. Hypothermia therapy is commonly used to treat secondary brain injury resulting from cardiac arrest. Previous studies have shown that CIRP is induced in specific brain regions during hypothermia and inhibits mitochondrial apoptotic factors. However, the specific mechanisms by which hypothermia-induced CIRP exerts its anti-apoptotic effect are still unknown. This study aims to investigate the role of Cold-inducible RNA-binding protein (CIRP) in mitochondrial-associated endoplasmic reticulum membrane (MAM)-mediated Ca2+ transport during hypothermic brain resuscitation.We constructed a rat model of cardiac arrest and resuscitation and hippocampal neuron oxygen-glucose deprivation/reoxygenation model. We utilized shRNA transfection to interfere the expression of CIRP and observe the effect of CIRP on the structure and function of MAM.Hypothermia induced CIRP can reduce the apoptosis of hippocampal neurons, and improve the survival rate of rats. Hypothermia induced CIRP can reduce the expressions of calcium transporters IP3R and VDAC1 in MAM, reduce the concentration of calcium in mitochondria, decrease the expression of ROS, and stabilize the mitochondrial membrane potential. Immunofluorescence and immunocoprecipitation showed that CIRP could directly interact with IP3R-VDAC1 complex, thereby changing the structure of MAM, inhibiting calcium transportation and improving mitochondrial function in vivo and vitro.Both in vivo and in vitro experiments have confirmed that hypothermia induced CIRP can act on the calcium channel IP3R-VDAC1 in MAM, reduce the calcium overload in mitochondria, improve the energy metabolism of mitochondria, and thus play a role in neuron resuscitation. This study contributes to understanding hypothermia therapy and identifies potential targets for brain injury treatment.

Keywords:  Brain resuscitation; Ca(2+) transport; Cold-inducible RNA-binding protein; Hypothermia; Mitochondrial-associated endoplasmic reticulum membrane; Neuroprotection

DOI:  https://doi.org/10.1016/j.expneurol.2024.114883
Trends Endocrinol Metab. 2024 Jul 06. pii: S1043-2760(24)00168-1. [Epub ahead of print]

Interorganelle phospholipid communication, a house not so divided.

Richard G Lee, Danielle L Rudler, Oliver Rackham, Aleksandra Filipovska.

  The presence of membrane-bound organelles with specific functions is one of the main hallmarks of eukaryotic cells. Organelle membranes are composed of specific lipids that govern their function and interorganelle communication. Discoveries in cell biology using imaging and omic technologies have revealed the mechanisms that drive membrane remodeling, organelle contact sites, and metabolite exchange. The interplay between multiple organelles and their interdependence is emerging as the next frontier for discovery using 3D reconstruction of volume electron microscopy (vEM) datasets. We discuss recent findings on the links between organelles that underlie common functions and cellular pathways. Specifically, we focus on the metabolism of ether glycerophospholipids that mediate organelle dynamics and their communication with each other, and the new imaging techniques that are powering these discoveries.

Keywords:  metabolic diseases; mitochondria; organelles; volume electron microscopy

DOI:  https://doi.org/10.1016/j.tem.2024.06.008
Cells. 2024 Jun 25. pii: 1100. [Epub ahead of print]13(13):

Daily Light Onset and Plasma Membrane Tethers Regulate Mitochondria Redistribution within the Retinal Pigment Epithelium.

Matilde V Neto, Giulia De Rossi, Bruce A Berkowitz, Miguel C Seabra, Philip J Luthert, Clare E Futter, Thomas Burgoyne.

  The retinal pigment epithelium (RPE) is an essential component of the retina that plays multiple roles required to support visual function. These include light onset- and circadian rhythm-dependent tasks, such as daily phagocytosis of photoreceptor outer segments. Mitochondria provide energy to the highly specialized and energy-dependent RPE. In this study, we examined the positioning of mitochondria and how this is influenced by the onset of light. We identified a population of mitochondria that are tethered to the basal plasma membrane pre- and post-light onset. Following light onset, mitochondria redistributed apically and interacted with melanosomes and phagosomes. In a choroideremia mouse model that has regions of the RPE with disrupted or lost infolding of the plasma membrane, the positionings of only the non-tethered mitochondria were affected. This provides evidence that the tethering of mitochondria to the plasma membrane plays an important role that is maintained under these disease conditions. Our work shows that there are subpopulations of RPE mitochondria based on their positioning after light onset. It is likely they play distinct roles in the RPE that are needed to fulfil the changing cellular demands throughout the day.

Keywords:  membrane contact sites; mitochondria; retinal pigment epithelium

DOI:  https://doi.org/10.3390/cells13131100
J Biol Chem. 2024 Jul 07. pii: S0021-9258(24)02035-0. [Epub ahead of print] 107534

The lipid droplet assembly complex consists of seipin and four accessory factors in budding yeast.

Chao-Wen Wang, Rey-Huei Chen, Yu-Kai Chen.

  Seipin, a crucial protein for cellular lipid droplet (LD) assembly, oligomerizes at the interface between the endoplasmic reticulum (ER) and LDs to facilitate neutral lipid packaging. Using proximity labeling, we identify four proteins-Ldo45, Ldo16, Tgl4, and Pln1-that are recruited to the vicinity of yeast seipin, the Sei1-Ldb16 complex, exclusively when seipin function is intact, hence termed seipin accessory factors. Localization studies identify Tgl4 at the ER-LD contact site, in contrast to Ldo45, Ldo16 and Pln1 at the LD surface. Cells with compromised seipin function resulted in uneven distribution of these proteins with aberrant LDs, supporting a central role of seipin in orchestrating their association with the LD. Overexpression of any seipin accessory factor causes LD aggregation and affects a subset of LD protein distribution, highlighting the importance of their stoichiometry. Although single factor mutations show minor LD morphology changes, combined mutations have additive effects. Lastly, we present evidence that seipin accessory factors assemble and interact with seipin in the absence of neutral lipids and undergo dynamically rearrangements during LD formation induction, with Ldo45 acting as a central hub recruiting other factors to interact with the seipin complex.

Keywords:  ER-LD contact site; LD assembly; Seipin; TurboID; lipid droplet; perilipin

DOI:  https://doi.org/10.1016/j.jbc.2024.107534
J Agric Food Chem. 2024 Jul 10.

Drp1 Aggravates Copper Nanoparticle-Induced ER-Phagy by Disturbing Mitochondria-Associated Membranes in Chicken Hepatocytes.

Quanwei Li, Pan Guo, Shaofeng Wang, Luna Su, Wenlan Yu, Jianying Guo, Liammei Hu, Hui Zhang, Jiaqiang Pan, Zhaoxin Tang, Jianzhao Liao.

  As an efficient alternative copper (Cu) source, copper nanoparticles (nano-Cu) have been widely supplemented into animal-producing food. Therefore, it is necessary to assess the effect of nano-Cu exposure on the biological health risk. Recently, the toxic effects of nano-Cu have been confirmed but the underlying mechanism remains unclear. This study reveals the impact of nano-Cu on endoplasmic reticulum autophagy (ER-phagy) in chicken hepatocytes and further identifies Drp1 and its downstream gene FAM134B as crucial regulators of nano-Cu-induced hepatotoxicity. Nano-Cu exposure can induce Cu ion overaccumulation and pathological injury in the liver, trigger excessive mitochondrial fission and mitochondria-associated membrane (MAM) integrity damage, and activate ER-phagy in vivo and in vitro. Interestingly, the knockdown of Drp1 markedly decreases the expression of FAM134B induced by nano-Cu. Furthermore, the expression levels of ATL3, CCPG1, SEC62, TEX264, and LC3II/LC3I induced by nano-Cu exposure are decreased by inhibiting the expression of Drp1. Simultaneously, the inhibition of FAM134B effectively alleviates nano-Cu-induced ER-phagy by downregulating the expression of ATL3, CCPG1, SEC62, TEX264, and LC3II/LC3I. Overall, these results suggest that Drp1-mediated impairment of MAM integrity leads to ER-phagy as a novel molecular mechanism involved in the regulation of nano-Cu-induced hepatotoxicity. These findings provide new ideas for future research on the mechanism of nano-Cu-induced hepatotoxicity.

Keywords:  ER-phagy; chicken; mitochondria-associated membrane; nano-Cu

DOI:  https://doi.org/10.1021/acs.jafc.4c03978
Cells. 2024 Jul 08. pii: 1162. [Epub ahead of print]13(13):

The Use of Hexokinase 2-Displacing Peptides as an Anti-Neoplastic Approach for Malignant Peripheral Nerve Sheath Tumors.

Francesco Ciscato, Ionica Masgras, Alessandro Gori, Marco Fantuz, Greta Bergamaschi, Denis Komarov, Martina La Spina, Shiva Ghasemi-Firouzabadi, Marco Pizzi, Angelo Paolo Dei Tos, Federica Chiara, Alessandro Carrer, Andrea Rasola.

  Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive sarcomas that can arise both sporadically and in patients with the genetic syndrome Neurofibromatosis type 1 (NF1). Prognosis is dismal, as large dimensions, risk of relapse, and anatomical localization make surgery poorly effective, and no therapy is known. Hence, the identification of MPNST molecular features that could be hit in an efficient and selective way is mandatory to envision treatment options. Here, we find that MPNSTs express high levels of the glycolytic enzyme Hexokinase 2 (HK2), which is known to shield cancer cells from noxious stimuli when it localizes at MAMs (mitochondria-associated membranes), contact sites between mitochondria and endoplasmic reticulum. A HK2-targeting peptide that dislodges HK2 from MAMs rapidly induces a massive death of MPNST cells. After identifying different matrix metalloproteases (MMPs) expressed in the MPNST microenvironment, we have designed HK2-targeting peptide variants that harbor cleavage sites for these MMPs, making such peptides activatable in the proximity of cancer cells. We find that the peptide carrying the MMP2/9 cleavage site is the most effective, both in inhibiting the in vitro tumorigenicity of MPNST cells and in hampering their growth in mice. Our data indicate that detaching HK2 from MAMs could pave the way for a novel anti-MPNST therapeutic strategy, which could be flexibly adapted to the protease expression features of the tumor microenvironment.

Keywords:  Neurofibromatosis type 1; hexokinase 2; hexokinase 2 targeting peptides; malignant peripheral nerve sheath tumors

DOI:  https://doi.org/10.3390/cells13131162
Aging Cell. 2024 Jul 12. e14273

Cytochrome b5 reductase 3 overexpression and dietary nicotinamide riboside supplementation promote distinctive mitochondrial alterations in distal convoluted tubules of mouse kidneys during aging.

M Pérez-Rodríguez, A García-Verdugo, L M Sánchez-Mendoza, A Muñoz-Martín, N Bolaños, C Pérez-Sánchez, J A Moreno, M I Burón, R de Cabo, J A González-Reyes, J M Villalba.

  The kidney undergoes structural and physiological changes with age, predominantly studied in glomeruli and proximal tubules. However, limited knowledge is available about the impact of aging and anti-aging interventions on distal tubules. In this study, we investigated the effects of cytochrome b5 reductase 3 (CYB5R3) overexpression and/or dietary nicotinamide riboside (NR) supplementation on distal tubule mitochondria. Initially, transcriptomic data were analyzed to evaluate key genes related with distal tubules, CYB5R3, and NAD+ metabolism, showing significant differences between males and females in adult and old mice. Subsequently, our emphasis focused on assessing how these interventions, that have demonstrated the anti-aging potential, influenced structural parameters of distal tubule mitochondria, such as morphology and mass, as well as abundance, distance, and length of mitochondria-endoplasmic reticulum contact sites, employing an electron microscopy approach. Our findings indicate that both interventions have differential effects depending on the age and sex of the mice. Aging resulted in an increase in mitochondrial size and a decrease in mitochondrial abundance in males, while a reduction in abundance, size, and mitochondrial mass was observed in old females when compared with their adult counterparts. Combining both the interventions, CYB5R3 overexpression and dietary NR supplementation mitigated age-related changes; however, these effects were mainly accounted by NR in males and by transgenesis in females. In conclusion, the influence of CYB5R3 overexpression and dietary NR supplementation on distal tubule mitochondria depends on sex, genotype, and diet. This underscores the importance of incorporating these variables in subsequent studies to comprehensively address the multifaceted aspects of aging.

Keywords:  aging; cytochrome b5 reductase 3; distal convoluted tubules; mitochondria; mitochondria‐endoplasmic reticulum contact sites; nicotinamide riboside; quantitative transmission electron microscopy; transcriptomics

DOI:  https://doi.org/10.1111/acel.14273
Mol Cell. 2024 Jun 28. pii: S1097-2765(24)00512-4. [Epub ahead of print]

Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.

Johannes Pilic, Benjamin Gottschalk, Benjamin Bourgeois, Hansjörg Habisch, Zhanat Koshenov, Furkan E Oflaz, Yusuf C Erdogan, Seyed M Miri, Esra N Yiğit, Mehmet Ş Aydın, Gürkan Öztürk, Emrah Eroglu, Varda Shoshan-Barmatz, Tobias Madl, Wolfgang F Graier, Roland Malli.

  Metabolic enzymes can adapt during energy stress, but the consequences of these adaptations remain understudied. Here, we discovered that hexokinase 1 (HK1), a key glycolytic enzyme, forms rings around mitochondria during energy stress. These HK1-rings constrict mitochondria at contact sites with the endoplasmic reticulum (ER) and mitochondrial dynamics protein (MiD51). HK1-rings prevent mitochondrial fission by displacing the dynamin-related protein 1 (Drp1) from mitochondrial fission factor (Mff) and mitochondrial fission 1 protein (Fis1). The disassembly of HK1-rings during energy restoration correlated with mitochondrial fission. Mechanistically, we identified that the lack of ATP and glucose-6-phosphate (G6P) promotes the formation of HK1-rings. Mutations that affect the formation of HK1-rings showed that HK1-rings rewire cellular metabolism toward increased TCA cycle activity. Our findings highlight that HK1 is an energy stress sensor that regulates the shape, connectivity, and metabolic activity of mitochondria. Thus, the formation of HK1-rings may affect mitochondrial function in energy-stress-related pathologies.

Keywords:  ER-mitochondria contact sites; energy stress; glucose starvation; glycolysis; hexokinase; live-cell imaging; mitochondrial constriction; mitochondrial fission; non-catalytic functions; protein cluster

DOI:  https://doi.org/10.1016/j.molcel.2024.06.009
Bioessays. 2024 Jul 11. e2400026

The physical basis of analog-to-digital signal processing in the EGFR system-Delving into the role of the endoplasmic reticulum.

Laura Zoe Kreplin, Senthil Arumugam.

  Receptor tyrosine kinases exhibit ligand-induced activity and uptake into cells via endocytosis. In the case of epidermal growth factor (EGF) receptor (EGFR), the resulting endosomes are trafficked to the perinuclear region, where dephosphorylation of receptors occurs, which are subsequently directed to degradation. Traveling endosomes bearing phosphorylated EGFRs are subjected to the activity of cytoplasmic phosphatases as well as interactions with the endoplasmic reticulum (ER). The peri-nuclear region harbors ER-embedded phosphatases, a component of the EGFR-bearing endosome-ER contact site. The ER is also emerging as a central player in spatiotemporal control of endosomal motility, positioning, tubulation, and fission. Past studies strongly suggest that the physical interaction between the ER and endosomes forms a reaction "unit" for EGFR dephosphorylation. Independently, endosomes have been implicated to enable quantization of EGFR signals by modulation of the phosphorylation levels. Here, we review the distinct mechanisms by which endosomes form the logistical means for signal quantization and speculate on the role of the ER.

Keywords:  endosomes; morphogen; signal interpretation

DOI:  https://doi.org/10.1002/bies.202400026
Int J Mol Sci. 2024 Jun 22. pii: 6878. [Epub ahead of print]25(13):

Lipid Droplet-Mitochondria Contacts in Health and Disease.

Hongjun Fan, Yanjie Tan.

  The orchestration of cellular metabolism and redox balance is a complex, multifaceted process crucial for maintaining cellular homeostasis. Lipid droplets (LDs), once considered inert storage depots for neutral lipids, are now recognized as dynamic organelles critical in lipid metabolism and energy regulation. Mitochondria, the powerhouses of the cell, play a central role in energy production, metabolic pathways, and redox signaling. The physical and functional contacts between LDs and mitochondria facilitate a direct transfer of lipids, primarily fatty acids, which are crucial for mitochondrial β-oxidation, thus influencing energy homeostasis and cellular health. This review highlights recent advances in understanding the mechanisms governing LD-mitochondria interactions and their regulation, drawing attention to proteins and pathways that mediate these contacts. We discuss the physiological relevance of these interactions, emphasizing their role in maintaining energy and redox balance within cells, and how these processes are critical in response to metabolic demands and stress conditions. Furthermore, we explore the pathological implications of dysregulated LD-mitochondria interactions, particularly in the context of metabolic diseases such as obesity, diabetes, and non-alcoholic fatty liver disease, and their potential links to cardiovascular and neurodegenerative diseases. Conclusively, this review provides a comprehensive overview of the current understanding of LD-mitochondria interactions, underscoring their significance in cellular metabolism and suggesting future research directions that could unveil novel therapeutic targets for metabolic and degenerative diseases.

Keywords:  disease; lipid droplet; metabolism; mitochondria; redox

DOI:  https://doi.org/10.3390/ijms25136878
Cardiovasc Diabetol. 2024 Jul 08. 23(1): 239

Myocardial transcriptomic analysis of diabetic patients with aortic stenosis: key role for mitochondrial calcium signaling.

Maelle Cherpaz, Emmanuelle Meugnier, Gaultier Seillier, Matteo Pozzi, Romain Pierrard, Simon Leboube, Fadi Farhat, Marco Vola, Jean-François Obadia, Camille Amaz, Lara Chalabreysse, Chloe May, Stephanie Chanon, Camille Brun, Lucas Givre, Gabriel Bidaux, Nathan Mewton, Genevieve Derumeaux, Cyrille Bergerot, Melanie Paillard, Helene Thibault.

  BACKGROUND: Type 2 diabetes (T2D) is a frequent comorbidity encountered in patients with severe aortic stenosis (AS), leading to an adverse left ventricular (LV) remodeling and dysfunction. Metabolic alterations have been suggested as contributors of the deleterious effect of T2D on LV remodeling and function in patients with severe AS, but so far, the underlying mechanisms remain unclear. Mitochondria play a central role in the regulation of cardiac energy metabolism.OBJECTIVES: We aimed to explore the mitochondrial alterations associated with the deleterious effect of T2D on LV remodeling and function in patients with AS, preserved ejection fraction, and no additional heart disease.
METHODS: We combined an in-depth clinical, biological and echocardiography phenotype of patients with severe AS, with (n = 34) or without (n = 50) T2D, referred for a valve replacement, with transcriptomic and histological analyses of an intra-operative myocardial LV biopsy.
RESULTS: T2D patients had similar AS severity but displayed worse cardiac remodeling, systolic and diastolic function than non-diabetics. RNAseq analysis identified 1029 significantly differentially expressed genes. Functional enrichment analysis revealed several T2D-specific upregulated pathways despite comorbidity adjustment, gathering regulation of inflammation, extracellular matrix organization, endothelial function/angiogenesis, and adaptation to cardiac hypertrophy. Downregulated gene sets independently associated with T2D were related to mitochondrial respiratory chain organization/function and mitochondrial organization. Generation of causal networks suggested a reduced Ca2+ signaling up to the mitochondria, with the measured gene remodeling of the mitochondrial Ca2+ uniporter in favor of enhanced uptake. Histological analyses supported a greater cardiomyocyte hypertrophy and a decreased proximity between the mitochondrial VDAC porin and the reticular IP3-receptor in T2D.
CONCLUSIONS: Our data support a crucial role for mitochondrial Ca2+ signaling in T2D-induced cardiac dysfunction in severe AS patients, from a structural reticulum-mitochondria Ca2+ uncoupling to a mitochondrial gene remodeling. Thus, our findings open a new therapeutic avenue to be tested in animal models and further human cardiac biopsies in order to propose new treatments for T2D patients suffering from AS.
TRIAL REGISTRATION: URL: https://www.
CLINICALTRIALS: gov ; Unique Identifier: NCT01862237.

Keywords:  HFpEF; MAM; MCU; MICU1; Mitochondria; Mitochondria-associated membranes; Pressure overload; RNAseq

DOI:  https://doi.org/10.1186/s12933-024-02329-5